Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
MEDICAMENT SUSTAINED-RELEASE PARTICLES AND
METHOD FOR PREPARING THE SAME
TECHNICAL FIELD
The present invention relates to particles for
sustainedly releasing a medicament, in particular, particles that
sustainedly release theophylline, and a method for preparing such
particles.
BACKGROUND OF THE INVENTION
To control the rate of medicament release, and to
enhance storage stability and taste-masking effect, various
pharmaceutical preparations have been disclosed in which low-
melting-point substances (for example, polyglycerol fatty acid
esters and glycerol fatty acid esters) are used as matrix base
materials.
For example, Japanese Patent No. 2893191 discloses a
method for obtaining spherical particles which comprises the
steps of fusing a polyglycerol fatty acid-containing matrix,
mixing the fused matrix with a medicament, and granulating the
mixture by spray-chilling. According to this patent, due to the
polyglycerol fatty acid ester, a pharmaceutical preparation with
stably controlled medicament release can be prepared. The patent
also discloses that by adjusting the HLB (hydrophilic-lipophilic
balance) of the polyglycerol fatty acid ester, the rate of
medicament release can be controlled.
Japanese Unexamined Patent Publication No. 505841/1996
discloses a drug delivery system with substantially no taste that
comprises a medicament with an unpleasant taste, a low-melting-
point substance and a hydrophobic polymer.
Japanese Examined Patent Publication No. 47531/1994
discloses particles with a sustained procainamide hydrochloride
release prepared by adhering procainamide hydrochloride to the
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surface of a low-melting-point substance nucleus with heating and,
while maintaining the temperature at the melting point of the
low-melting-point substance or higher, and adhering talc to
surface thereof. This sustained-release particulate is said to
have excellent sustained release properties, appearance, strength,
stability, etc.
Japanese Patent No. 3124063 discloses particles
prepared by heating a granular polyglycerol fatty acid ester
having a melting point of 40-80 C and a powder to fluidize them,
thereby reportedly enabling the active ingredient contained in
the powder to be steadily released and rendering the active
ingredient stabilized over a long period of time.
DISCLOSURE OF THE INVENTION
As a result of their own research of the pharmaceutical
preparations disclosed in the aforementioned prior art
publications, however, the invention found disadvantages as
described hereinbelow:
(a) Japanese Patent No. 2893191 discloses a method for
preparing particles of a matrix formulation, comprising the steps
of heating and mixing a pharmacologically active substance and a
matrix base material containing a polyglycerol fatty acid to give
a molten mixture, and granulating the molten mixture by spray-
chilling. In this method, it was found that when theophylline was
used as the pharmacologically active substance, the resulting
molten mixture showed a significantly high viscosity, thereby
making uniform stirring and mixing difficult. In particular, this
tendency was more pronounced when a high proportion of
polyglycerol fatty acid ester was contained as the matrix base
material. Therefore, it was almost impossible to prepare core
particles, with theophylline being uniformly dispersed in the
matrix of each core particle, and the core particles obtained did
not attain a stably controlled medicament releasability (see, for
example, Test Example 1).
(b) The inventors prepared core particles containing a
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pharmacologically active substance and a matrix base material
composed of a polyglycerol fatty acid ester having a low
hydrophilic-lipophilic balance (HLB) as disclosed in Japanese
Patent Publication No. 2893191, and attempted to fusion-coat the
core particles with a fine powder of talc or the like while
heating and agitating. The inventors found that before the
product temperature reached the melting point, i.e., before the
core particles were coated with the fine powder, the core
particles electrostatically adhered to the inner walls of a
mixer/granulator, and the accumulation of the adhered core
particles thickened, thereby impairing the efficiency of
agitating the ingredients, decreasing thermal conductivity to the
core particles, and making it difficult to completely fusion-coat
the surface of the core particles with the fine powder, thereby
leading to a reduced product yield (see, for example, Test
Example 2).
Accordingly, a primary object of the present invention
is to overcome disadvantage (a), i.e., to enhance the mixing
efficiency by lowering the viscosity of a molten mixture
containing a polyglycerol fatty acid ester and theophylline as
well as to obtain homogenous particles of a matrix formulation
having a stably controlled medicament releasability
(dissolvability) . Herein the phrase "stably controlled medicament
releasability (dissolvability)" refers to exhibiting
substantially no time dependent change in the rate of medicament
release (dissolution) after the pharmaceutical preparation has
been stored for a long period of time, thus retaining the
property of sustained release (dissolution).
Another primary object of the present invention is to
overcome disadvantage (b), i.e., when a fine powder is applied by
fusion coating to core particles containing a polyglycerol fatty
acid ester used as a matrix base material, to inhibit the core
particles from electrostatically adhering to the inner walls of a
granulator due to the matrix base material to efficiently perform
the fusion coating process, and to obtain particles of a matrix
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formulation having a stably controlled medicament releasability
(dissolvability).
The inventors conducted extensive research to overcome
disadvantage (a) and found that by adding a specific amount of
ethyl cellulose (hereinafter sometimes referred to as "EC") to a
molten mixture of a polyglycerol fatty acid ester and
theophylline, the viscosity of the molten mixture can be
drastically decreased. The inventors conducted further research
based on this finding and accomplished the present invention.
In particular, the present invention provides
theophylline sustained release particles and methods for
preparing the same (hereinafter sometimes referred to as the
"first embodiment") as follows:
Item 1. A method for preparing theophylline sustained release
particles comprising
heating a matrix base material comprising a
polyglycerol fatty acid ester, theophylline and ethyl cellulose
to give a liquefied mixture; and
granulating the liquefied mixture by spray-cooling.
Item 2. The method according to Item 1 comprising
heating a matrix base material comprising a
polyglycerol fatty acid ester, theophylline and ethyl cellulose
to give a liquefied mixture;
granulating the liquefied mixture by spray-cooling to
obtain spherical core particles; and
applying fine powder to the core particles by fusion
coating.
Item 3. The method according to Item 2, wherein the core
particles have a theophylline content of about 8 to about 50 wt.%
and an ethyl cellulose content of about 0.01 to about 5 wt.%, and
the fine powder is applied to the core particles in an amount of
about 5 to about 50 parts by weight per 100 parts by weight of
the core particles.
Item 4. The method according to Item 2 or 3, wherein the core
particles have an average particle diameter of 250 m or less,
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and the theophylline sustained release particles obtained by
fusion coating have an average particle diameter of 450 }im or
less.
Item 5. The method according to any one of Items 1-4, wherein
the polyglycerol fatty acid ester is a polyglycerol fatty acid
half ester.
Item 6. The method according to any one of Items 1-5, wherein
the polyglycerol fatty acid ester is a triglycerol behenic acid
half ester.
Item 7. The method according to Item 1 or 2, wherein the matrix
base material further contains a glycerol fatty acid ester.
Item 8. The method according to Item 7, wherein the glycerol
fatty acid ester is at least one member selected from the group
consisting of a glycerol behenic acid ester and glycerol stearic
acid ester.
Item 9. The method according to Item 8, wherein the glycerol
fatty acid ester is a glycerol behenic acid ester.
Item 10. The method according to any one of Items 2-9, wherein
the fusion coating is performed using agitation method.
Item 11. The method according to any one of Items 2-10, wherein
the fusion coating is performed at a temperature in the vicinity
of the melting point or the softening point of the matrix base
material.
Item 12. The method according to any one of Items 1-11, wherein
the matrix base material has a hydroxyl value of about 60 or
greater.
Item 13. The method according to any one of Items 2-12, wherein
the fine powder is at least one member selected from the group
consisting of talc, magnesium stearate, titanium oxide, ethyl
cellulose, calcium stearate and cellulose acetate.
Item 14. The method for preparing theophylline sustained release
particles according to Item 2 further comprising the step of heat
treatment after the fusion coating.
Item 15. The method according to Item 2 further comprising
subjecting the core particles to a heat treatment before the
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fusion coating.
Item 16. The method according to Item 14 or 15, wherein the heat
treatment is conducted at a temperature from about 40 C to about
the melting point or the softening point of the matrix base
material.
Item 17. Theophylline sustained release particles obtainable by
the method according to any one of Items 1-16.
Item 18. Particles comprising a matrix base material containing
a polyglycerol fatty acid ester, theophylline and ethyl cellulose,
the theophylline and ethyl cellulose being uniformly
dispersed throughout the matrix base material.
Item 19. Theophylline sustained release particles each
comprising the particle of Item 18 as nucleus particle and a
coating layer comprising a fine powder formed around the nucleus
particle.
Item 20. The theophylline sustained release particles according
to any one of Items 17-19 having a 2-hour theophylline
dissolution rate of about 15 to about 55%, a 4-hour dissolution
rate of about 25 to about 70% and a 6-hour dissolution rate of
about 50 to about 95%, as measured according to The Japanese
Pharmacopoeia, 14th Edition, Dissolution Test (2nd Method, Paddle
Method) at a stirring speed of 75 rpm using water or a 0.5%
aqueous polysorbate 80 solution as test solution.
Moreover, the inventors conducted extensive research to
overcome disadvantage (b) and found that by using a matrix base
material having a specific hydroxyl value, the occurrence of
electrostatic adhesion of core particles upon fusion coating can
be inhibited. The inventors conducted further research based on
this finding and accomplished the present invention.
In particular, the present invention provides
medicament sustained release particles and methods for preparing
them (hereinafter sometimes referred to as the "second
embodiment") as follows:
Item 21. A method for preparing medicament sustained release
particles comprising applying a fine powder by fusion coating to
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core particles containing a pharmacologically active substance
and a matrix base material that has a hydroxyl value of 60 or
greater and contains a polyglycerol fatty acid ester.
Item 22. The method according to Item 21 comprising
heating a pharmacologically active substance and a
matrix base material that has a hydroxyl value of 60 or greater
and contains a polyglycerol fatty acid ester to thereby give a
liquefied mixture,
granulating the liquefied mixture by spray-cooling to
obtain spherical core particles; and
applying fine particles to the core particles by fusion
coating.
Item 23. The method according to Item 21 or 22, wherein the
fusion coating is performed at a temperature in the vicinity of
the melting point or the softening point of the matrix base
material.
Item 24. The method according to any one of Items 21-23, wherein
the matrix base material has a hydroxyl value of about 80 to
about 350.
Item 25. The method according to any one of Items 21-24 further
comprising a heat treatment step after the fusion coating.
Item 26. The method according to any one of Items 21-24 further
comprising subjecting the core particles to heat treatment before
the fusion coating.
Item 27. The method according to Item 25 or 26, wherein the heat
treatment is conducted at a temperature from about 400 C to about
the melting point or the softening point of the matrix base
material.
Item 28. The method according to any one of Items 21-27, wherein
the polyglycerol fatty acid ester is a polyglycerol fatty acid
half ester.
Item 29. The method according to any one of Items 21-27, wherein
the polyglycerol fatty acid ester is a triglycerol behenic acid
half ester.
Item 30. Medicament sustained release particles obtainable by
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the method according to any one of Items 21-29.
Item 31. Particles comprising a pharmacologically active
substance and a matrix base material having a hydroxyl value of
60 or greater and containing a polyglycerol fatty acid ester,
the pharmacologically active substance being uniformly
dispersed throughout the matrix base material.
Item 32. Medicament sustained release particles each
comprising the particle of Item 31 as nucleus particle and a
coating layer comprising a fine powder and formed around the
nucleus particle.
According to an embodiment of the present invention,
there is provided a method for preparing a sustained
release particle formulated for use as a medicament
comprising applying a fine powder by fusion coating to a
core particle containing a pharmacologically active
substance and a matrix base material that has a hydroxyl
value of 60 or greater and contains a polyglycerol fatty
acid ester, wherein the fine powder is talc, magnesium
stearate, titanium oxide, ethyl cellulose, calcium
stearate, cellulose acetate, or a pharmacologically active
substance, or any combination thereof.
According to another embodiment of the present
invention, there is provided a sustained release particle
formulated for use as a medicament, comprising
a core particle comprising a pharmacologically active
substance and a matrix base material having a hydroxyl
value of 60 or greater and a polyglycerol fatty acid ester,
wherein the pharmacologically active substance is uniformly
dispersed throughout the matrix base material, and
a coating layer comprising a fine powder formed around
the core particle by fusion coating, wherein the fine powder
is talc, magnesium stearate, titanium oxide, ethyl cellulose,
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calcium stearate, cellulose acetate, or a pharmacologically
active substance, or a combination thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the theophylline
dissolution of the heat-treated fusion-coated particles of
Comparative Example 17.
Figure 2 is a graph showing the theophylline
dissolution of the heat-treated fusion-coated particles of
Example 28.
Figure 3 is a graph showing the theophylline
dissolution of the non-heat-treated fusion-coated particles of
Example 25.
Figure 4 is a graph showing the theophylline
dissolution of the non-heat-treated fusion-coated particles of
Example 28.
Figure 5 is a graph comparing the theophylline
dissolution of particles fusion-coated by an agitation method
with the theophylline dissolution of particles fusion-coated by a
fluid-bed method.
DETAILED DESCRIPTION OF THE INVENTION
Theophylline sustained release particles and methods
for preparing them (first embodiment), and medicament sustained
release particles and methods for preparing them (second
embodiment) will be described hereinbelow.
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A. Theophylline sustained release particles and Methods for
Preparing Them (first embodiment)
The theophylline sustained release particles of the
present invention are in the form of a matrix formulation
containing theophylline. This sustained-release matrix
formulation is in the form of particles and has a stably
controlled theophylline releasability since theophylline is
uniformly dispersed throughout the matrix. The theophylline
sustained release particles of the present invention encompass
core particles containing theophylline in a matrix, fusion-coated
particles prepared by fusion coating such core particles with a
fine powder such as talc powder or the like, and similar
particles subjected to any necessary dilution process.
A-1. Core particles
Theophylline
The core particles of the sustained-release particles
of the present invention contain theophylline as a
pharmacologically active substance. Theophylline can be either
crystalline or amorphous in form. The core particles have a
theophylline content of about 8 to about 50 wt.%, preferably
about 15 to about 50 wt.% and more preferably about 20 to about
50 wt.%.
Matrix
The matrix of the core particles of the present
invention contains a matrix base material containing a
polyglycerol fatty acid ester as a main ingredient and further
contains ethyl cellulose, and if desired other additives. The
matrix base material may contain a glycerol fatty acid ester and
the like in addition to the polyglycerol fatty acid ester.
Polyglycerol Fatty Acid Esters
The polyglycerol fatty acid ester used as the matrix
base material is a fatty acid ester of polyglycerol.
Specific examples of polyglycerols are those that have
a polymerization degree of 2-10, preferably 3-10. Usable are, for
example, diglycerol, triglycerol, tetraglycerol, pentaglycerol,
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hexaglycerol, heptaglycerol, octaglycerol, nonaglycerol,
decaglycerol, etc. Particularly usable are triglycerol,
tetraglycerol, pentaglycerol, hexaglycerol, heptaglycerol,
octaglycerol, nonaglycerol, decaglycerol, etc.
Usable fatty acids are, for example, saturated or
unsaturated higher fatty acids having 12-22 carbon atoms and
preferably 18-22 carbon atoms. Palmitic acid, stearic acid, oleic
acid, linoleic acid, linolenic acid, myristic acid, lauric acid,
ricinoleic acid, behenic acid and the like are usable as such
fatty acids. In particular, stearic acid, oleic acid, behenic
acid, ricinoleic acid and like saturated and unsaturated higher
fatty acids having 18-22 carbon atoms are generally used.
A usable polyglycerol fatty acid ester is that in which
C12-22 fatty acid(s) are linked to the aforementioned polyglycerol
with at least 1 hydroxyl group remaining therein. Specific
examples of polyglycerol fatty acid esters are triglycerol
behenic acid esters, triglycerol stearic acid esters,
tetraglycerol behenic acid esters, tetraglycerol stearic acid
esters, pentaglycerol behenic acid esters, pentaglycerol stearic
acid esters, hexaglycerol behenic acid esters, hexaglycerol
stearic acid esters, heptaglycerol behenic acid esters,
heptaglycerol stearic acid esters, octaglycerol behenic acid
esters, octaglycerol stearic acid esters, nonaglycerol behenic
acid esters, nonaglycerol stearic acid esters, decaglycerol
behenic acid esters, decaglycerol stearic acid esters and the
like. Such esters can be used singly or as a mixture of 2 or more
species. According to the number of hydroxyl groups in the
polyglycerol, the polyglycerol fatty acid esters are categorized
as fatty acid monoesters, diesters, triesters, tetraesters,
pentaesters, hexaesters, half esters, etc.
Among these polyglycerol fatty acid esters,
polyglycerol fatty acid half esters are preferable. In particular,
triglycerol behenic acid half esters, tetraglycerol behenic acid
half esters, pentaglycerol behenic acid half esters, hexaglycerol
behenic acid half esters, heptaglycerol behenic acid half esters,
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octaglycerol behenic acid half esters, nonaglycerol behenic acid
half esters, decaglycerol behenic acid half esters and like
polyglycerol behenic acid half esters; and triglycerol stearic
acid half esters, tetraglycerol stearic acid half esters,
pentaglycerol stearic acid half esters, hexaglycerol stearic acid
half esters, heptaglycerol stearic acid half esters, octaglycerol
stearic acid half esters, nonaglycerol stearic acid half esters,
decaglycerol stearic acid half esters and like polyglycerol
stearic acid half esters are more preferably used. Triglycerol
behenic acid half esters are most preferably used.
In the present specification and claims, polyglycerol
fatty acid esters in which all the hydroxyl groups in a
polyglycerol are esterified with fatty acids are referred to as
polyglycerol fatty acid "full" esters, and polyglycerol fatty
acid esters in which about half of the hydroxyl groups in the
polyglycerol are esterified with fatty acids are referred to as
polyglycerol fatty acid "half" esters. With respect to
polyglycerol fatty acid esters other than the "polyglycerol fatty
acid full esters", which hydroxyl groups in the polyglycerol are
esterified are not limited; any given hydroxyl group may be
esterified.
Specifically, a "polyglycerol fatty acid half ester"
refers to a polyglycerol fatty acid ester or a mixture thereof in
which the average number (NE) of esterified hydroxyl groups in the
polyglycerol is about the half of the number (N) of hydroxyl
groups present in the non-esterified polyglycerol. Such
polyglycerol fatty acid half esters have 0.3<-NE/N:!~0.7, and
preferably 0.35<NE/N:-0.65 .
For example, a triglycerol behenic acid half ester
means an ester in which 2 or 3 behenic acids are ester-linked to
a triglycerol having 5 hydroxyl groups, the triglycerol being 3
glycerol molecules dehydratively condensed, or a mixture thereof,
i.e., triglycerol behenic acid (di or tri) ester.
The molecular weight of the polyglycerol fatty acid
esters is usually 200-5000, preferably 300-2000 and more
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preferably 500-2000. Preferable are polyglycerol fatty acid
esters that are solid at ordinary temperature (about 15 C) and
have a melting point of 15-90 C, and more preferably 45-80 C.
Such polyglycerol fatty acid esters usable herein can be a
mixture of 2 or more compounds. In such a case, even when a
liquid polyglycerol fatty acid ester is partially contained, such
a mixture is usable if it as a whole is solid at ordinary
temperatures. The core particles have a polyglycerol fatty acid
ester content of about 20 to about 90 wt.%, preferably about 25
to about 80 wt.% and more preferably about 30 to about 70 wt.%.
Glycerol Fatty Acid Esters
The glycerol fatty acid ester optionally used as a
secondary ingredient of the matrix base material is a mono-, di-
or tri C12_22 fatty acid ester of a glycerol. Preferable glycerol
fatty acid esters include glycerol behenic acid esters, glycerol
stearic acid esters, glycerol lauric acid esters, glycerol
palmitic acid esters, etc. If necessary, 2 or more glycerol fatty
acid esters may be used in the matrix base material. Among such
esters, glycerol behenic acid esters and glycerol stearic acid
esters are preferable. Specific examples are glycerol stearic
acid monoester, glycerol stearic acid diester, glycerol stearic
acid triester, glycerol behenic acid monoester, glycerol behenic
acid diester, glycerol behenic acid triester, etc. Among these,
glycerol behenic acid esters are preferable, with glycerol
behenic acid monoester, glycerol behenic acid diester and their
mixtures being especially preferable.
The core particles have a glycerol fatty acid ester
content of 0 to about 60 wt.%, preferably about 1 to about 50
wt.% and more preferably 2 to about 40 wt.%. The matrix base
material preferable in the present invention contains both a
glycerol fatty acid ester and a polyglycerol fatty acid ester.
Hydroxyl Value of Matrix base material
The matrix base material usable in the present
invention can be prepared to have a hydroxyl value of about 60 or
greater, preferably about 80 to about 350 and more preferably
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about 100 to about 300. Due to such a hydroxyl value, the core
particles can be inhibited from electrostatically adhering to the
inner walls of a granulator in the fusion coating process
described hereinbelow, thereby allowing efficient fusion coating
and the production of particles of a matrix formulation having a
stably-controlled medicament releasability. The term "hydroxyl
value" as used herein is defined in Syokuhin Tenkabutsu Kouteisho
"Yushirui Shiken Hou" (The Japanese Standards for Food Additives
"Testing Methods for Fats and Oils"), Hirokawa Shoten, 1999, B-
195. In particular, the term "hydroxyl value" refers to, when the
hydroxyl groups of a 1 g sample are acetylated, the amount (mg)
of potassium hydroxide (KOH) necessary to neutralize acetic acid
equivalent to acetyl group(s).
With respect to pharmaceutical preparations that
sustainedly release pharmacologically active substances, it is
generally considered preferable, to use polyglycerol fatty acid
esters having a low hydrophilic-lipophilic balance (HLB) for the
matrix to suppress the dissolution from the core particles.
However, when the HLB of the matrix is low, the hydroxyl value is
accordingly low, which results in a more pronounced tendency to
electrostatically adhere to the inner walls of a granulator when
fusion coating. To prevent this electrostatic adhesion, it is
necessary to use core particles that barely accumulate an
electrostatic charge. As a solution to this problem, a matrix
base material having a hydroxyl value of preferably 60 or greater
is used.
Glycerol fatty acid esters by themselves, especially
monoglycerides (monoesters), barely adhere electrostatically to a
granulator due to their high hydroxyl values. However, glycerol
fatty acid esters and like lipids undergo crystalline transitions,
thereby making it difficult to prepare stable pharmaceutical
preparations. To inhibit crystalline transitions, it is
preferable to have in the matrix base material 50 wt.% or more
polyglycerol fatty acid ester. Therefore, the hydroxyl value of
the polyglycerol fatty acid ester in the matrix base material is
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especially important. Hence, the hydroxyl value of the
polyglycerol fatty acid ester should be controlled to be
preferably about 60 or greater, more preferably about 80 to about
350 and particularly preferably about 100 to about 300.
Ethyl Cellulose
Ethyl cellulose is contained in the matrix of the core
particles of the present invention. As described in the
Disclosure of the Invention (a), when theophylline is added to a
molten mixture prepared by heating a matrix base material
containing a polyglycerol fatty acid ester, the viscosity of the
molten mixture is excessively increased, making uniform blending
difficult. This phenomenon is peculiar to theophylline when it is
used as a medicament. However, if a small amount of ethyl
cellulose is added to the theophylline-containing molten mixture,
the viscosity of the mixture is promptly decreased, thereby
drastically improving the workability with respect to stirring,
mixing, fluid pumping, etc., and allowing the production of a
uniformly blended molten mixture. By spray-cooling this molten
mixture, homogenous particles of a matrix formulation having a
stably controlled medicament releasability (dissolvability) can
be obtained.
The viscosity of the ethyl cellulose, determined as a
5% ethyl cellulose solution in 80% toluene and 20% ethanol (at
C), is usually preferably about 1 to about 100 cps, and
25 particularly preferably about 2 to about 50 cps.
The core particles should usually be prepared to have
an ethyl cellulose content of about 0.01 to about 5 wt.%, and
preferably about 0.1 to about 3 wt.%. When the ethyl cellulose
content is within this range, the desired decrease in the
viscosity of the molten mixture can be observed.
Additives
Insofar as the action and effects of the present
invention are not adversely affected, additives that are
typically used in the field of sustained-release pharmaceutical
preparations can be used in the matrix of the core particles of
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the present invention in addition to the compounds described
above. Examples include propylene glycol fatty acid esters,
sorbitan fatty acid esters, paraffin, microcrystalline wax,
ceresin, hydrogenated oil, Japan wax, cacao butter, carnauba wax,
beeswax, lecithin, cetanol, stearyl alcohol, myristic acid,
palmitic acid, stearic acid, titanium stearate, calcium oleate,
etc. These additives are contained in the core particles usually
in an amount of 50 wt.% or less, and preferably 40 wt.% or less.
Preferable Form of Core particles
Examples of preferable forms of the core particles of
the sustained theophylline release pharmaceutical preparation of
the present invention are given below.
Although the matrix base material may be composed of
just a polyglycerol fatty acid ester, it is preferable to also
have a glycerol fatty acid ester. A polyglycerol behenic acid
half ester is preferable as the polyglycerol fatty acid ester,
and a triglycerol behenic acid half ester is particularly
preferable. A glycerol behenic acid ester or glycerol stearic
acid ester is preferable as the glycerol fatty acid ester, and a
glycerol behenic acid monoester, a glycerol behenic acid diester
and a mixture thereof are especially preferable.
Even when such a matrix base material is used, it is
preferable to ensure 50 wt.% or greater of the entire weight of
the matrix base material in the core particles is the
polyglycerol fatty acid ester. It is sufficient that the weight
ratio of polyglycerol fatty acid ester/glycerol fatty acid ester
in the matrix base material is about 50/50 to about 95/5, and
preferably about 50/50 to about 90/10.
The core particles have a theophylline content of about
15 to about 50 wt.%, preferably about 20 to about 50 wt.% and
more preferably about 25 to about 45 wt.%. The core particles
have a polyglycerol fatty acid ester content of about 25 to about
80 wt.% and preferably about 30 to about 70 wt.%. The core
particles have a glycerol fatty acid ester content of about 1 to
about 50 wt.%, preferably about 2 to about 40 wt.% and more
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preferably about 5 to about 35 wt.%. The core particles have an
ethyl cellulose content of about 0.01 to about 5 wt.% and
preferably about 0.1 to about 3 wt.%.
A-2. Method for Preparing Core particles
The aforementioned core particles may be prepared as
follows:
The matrix base material containing the polyglycerol
fatty acid ester, theophylline and ethyl cellulose is heated to a
liquefied mixture (or a molten mixture) . This liquefied mixture
is spray-cooled for granulation to give spherical core particles.
The liquefied mixture includes a suspension mixture.
The temperature for fusing the matrix base material
containing the polyglycerol fatty acid ester is high, ranging
from the melting point (hereinafter sometimes referred to as "Tm")
of the matrix base material upwards, and preferably from (Tm
+10) C upwards, as long as such temperatures do not impair the
stability of theophylline. When the matrix base material is a
mixture, it may not exhibit a definite melting point. Therefore,
the softening temperature (softening point, hereinafter sometimes
referred to as "Ts") of the mixture can be substituted for the
aforementioned Tm.
Hereinafter, the melting point (T,,) or softening point
(Ts) of the matrix base material may sometimes be referred to as
"T", i.e., T = Tm or T.
To be able to uniformly dissolve (fuse) or disperse
throughout the matrix base material, powdery ethyl cellulose with
an average particle diameter of about 0.1 to about 200 pm, and
preferably about 0.5 to about 150 pm, is usually used.
To be able to uniformly disperse throughout the matrix
base material, powdery theophylline with an average particle
diameter of about 0.1 to about 100 pm, and preferably about 0.5
to about 50 pm, is usually used.
Average particle diameters can be measured according to
known methods such as laser light scattering and the like.
In the preparation of the molten mixture, the order of
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addition of theophylline and ethyl cellulose to the molten matrix
base material is not restricted. After dissolving or dispersing
theophylline in the molten matrix, ethyl cellulose may be
dissolved (fused) or dispersed therein. Likewise, after
dissolving (fusing) or dispersing ethyl cellulose in the molten
matrix base material, theophylline may be dissolved or dispersed
therein. Moreover, the dissolution or dispersion of theophylline
and the dissolution (fusion) or dispersion of ethyl cellulose in
the molten mixture can be carried out simultaneously.
When the theophylline sustained release particles of
the present invention are to be in the form of powders, granules,
microgranules, dry syrups, tablets, capsules and the like, a
method preferably employed for the preparation of the molten
mixture is heating and fusing the matrix base material, adding
ethyl cellulose and theophylline into the molten matrix base
material, and dissolving or dispersing the ethyl cellulose and
theophylline therein to give a molten mixture. An example of
particularly preferable method is adding premixed ethyl cellulose
and theophylline into a molten matrix base material, and
dissolving or dispersing to give a molten mixture.
The ingredients of the core particles are contained in
the amounts as described in "A-1. Core particles" above. As
described therein, in the method of the present invention, the
viscosity of the molten mixture is significantly decreased by
adding a small amount of ethyl cellulose, thereby allowing easy
stirring and mixing. Thus, theophylline can be uniformly
dispersed throughout the matrix base material, enabling the
preparation of homogenous particles of a matrix formulation
having a stably controlled medicament releasability
(dissolvability).
The core particles can be prepared by spray-cooling the
above-obtained molten mixture. Spray-cooling of the molten
mixture can be performed according to conventional methods using,
for example, a spray cooler equipped with a rotary disc,
pressurized spray nozzle, two-fluid spray nozzle, etc. Cooling
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may usually be performed at room temperature. Appropriate control
of the spraying conditions can give the desired diameter to the
particles.
The core particles obtained according to such spray-
cooling granulation are spherical, and their average particle
diameter is usually 250 jim or less, preferably 200 pm or less,
more preferably about 30 to about 200 jm, and particularly
preferably about 50 to about 180 pm. The average particle
diameter of the core particles can be measured according to known
methods such as sieving.
Although the core particles obtained above can be used
as they are in the fusion coating process that follows, they may
be subjected to a heat treatment prior to the fusion coating. The
heat treatment conditions are a temperature from about 40 C to
about T C at which the core particles do not fuse and adhere and
a period of 2-48 hours (in particular, about 3 to about 24 hours).
Due to this heat treatment, the crystalline transition of the
matrix base material can be enhanced and completed, thereby
enabling the theophylline release of the resulting product to be
stabilized and thus giving sustained-release particles excellent
storage stability.
The core particles of the present invention obtained as
described above have a makeup in which theophylline and ethyl
cellulose are uniformly dispersed throughout the matrix base
material. Specifically, it is not a layered structure in which
the theophylline and ethyl cellulose are localized at or adjacent
to the surface of the matrix base material particles; rather the
theophylline and ethyl cellulose are uniformly dispersed at the
molecular level or as fine particles throughout the entire
particles of the matrix base material, i.e., at the surface and
within the particle structure.
Herein, the phrase "uniformly dispersed at the
molecular level" means that theophylline, ethyl cellulose and the
ester matrix form a homogeneous mixture of solids (solid
dispersion) . The phrase "uniformly dispersed as fine particles"
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means that theophylline and ethyl cellulose are evenly scattered
as fine particles substantially throughout the entire matrix.
As described above, the core particles of the present
invention, due to theophylline being uniformly dispersed
throughout the matrix, can mask the bitterness of theophylline
despite having an average particle diameter of about 30 to about
200 pm (preferably about 50 to about 180 pm) and so are very
small, thereby enabling a stably controlled medicament
releasability to be retained. Furthermore, the matrix base
material is present at the surface of the core particles. This
structure is suitable for fusion coating as described hereinbelow.
A-3. Fusion Coating
Fusion Coating
Fine powder is applied by fusion coating to the above-
obtained core particles to further prepare the theophylline
sustained release particles of the present invention. At least
one member selected from, for example, talc, magnesium stearate,
titanium oxide, ethyl cellulose, calcium stearate and cellulose
acetate can be used as such a fine powder. Talc and ethyl
cellulose are preferable. Talc is particularly preferable.
Furthermore, if necessary, to eliminate any electrostatic charge
that may build up on the particles during fusion coating, light
anhydrous silicic acid and the like can be added. Unlike in spray
coating, organic solvents are not used in fusion coating.
When the core particles obtained according to "A-2.
Method for preparing core particles" are heated and fused, the
molten matrix base material oozes toward the nucleus particle
surface as a molten fluid. Due to the adhesiveness of the molten
fluid in this instance, any fine powder present in the vicinity
of the molten fluid adheres thereto. The fusion coating employed
in the present invention is a technique to form, by taking
advantage of the adhesiveness of the molten matrix base material,
a coating (covering) layer containing fine powder on the surface
of the core particles.
The average particle diameter of the fine powder varies
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according to the particle diameter of the core particles to be
fusion-coated, but it is usually smaller than the diameter of the
core particles. It is usually selected from the range of about 20
pm or smaller, preferably about 1 to about 15 pm and more
preferably about 1 to about 10 pm.
The mixing ratio of core particles and fine powder may
be determined according to the desired rate of theophylline
release, diameter of the core particles and desired diameter of
the end-product theophylline sustained release particles. The
fine powder is usually used in an amount of about 5 to about 50
parts by weight, preferably about 10 to about 50 parts by weight
and more preferably about 10 to about 45 parts by weight, per 100
parts by weight of core particles.
Fusion coating can be performed according to known
methods. For example, the fine powder may be blended with the
above-obtained core particles and heated while agitating. The
heating temperature is about the melting point (Tm) or softening
point (Ts) of the matrix base material, i.e., about T. The phrase
"about T" refers to the range of (T-15) C to T C, and preferably
(T-10) C to T C. For example, when the matrix base material is
composed of a polyglycerol fatty acid ester and a glycerol fatty
acid ester, it is in the range of about 40 to about 90 C, and
preferably about 45 to about 80 C. The duration of fusion coating
is, depending on the production scale, usually about 5 minutes to
about 5 hours.
In the present invention, it is recommended to apply a
fine powder to the core particles by fusion coating while
agitating, i.e., using agitation method. Japanese Patent
Publication No. 3124063 discloses a method in which powder is
fused and adhered to polyglycerol fatty acid ester particles in a
fluid bed. However, in fluid beds, to heat core particles to a
temperature near their melting point, hot air having a
temperature higher than the melting point is necessary, and
because of the high temperature of the fluid-bed apparatus (side
walls, meshed portion at the bottom, etc.) the core particles
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fuse, adhere to the apparatus, and aggregate, resulting in
impaired yields. Moreover, it is practically impossible to
tightly and completely affix powder to the core particles for the
purpose of sustained medicament release. In contrast, when
agitation method is employed, the container temperature (jacket
temperature) of the mixer can be desirably controlled to a
temperature substantially identical to the temperature of the
core particles. Moreover, the entire apparatus can be rapidly
cooled by introducing cold water into the jacket. Therefore, the
core particles are barely overheated, completely preventing the
core particles from aggregation due to fusion and adhesion to
sidewalls.
The core particles after fusion coating are spherical
and usually have an average particle diameter of 450 pm or less,
preferably 400 pm or less, more preferably about 30 to about 400
pm and particularly preferably about 50 to about 350 pm.
The fusion-coated particles thus obtained are
theophylline sustained release particles that have a fine-powder-
containing coating layer around their core particles.
Thermal Aftertreatment
Although the fusion-coated particles obtained above can
be brought as they are to the process that follows, it is
preferable to subject the fusion-coated particles to a heat
treatment beforehand. The heat treatment conditions are a
temperature from about 40 C to about T C at which the fusion-
coated particles do not fuse and cluster and a period of 2-48
hours (preferably about 3 to about 24 hours). Due to this heat
treatment, the crystalline transition of the matrix base material
can be enhanced and completed, thereby enabling the theophylline
release of the resulting product to be stabilized, and stable and
extended theophylline release to be maintained even after long-
term storage.
Specifically, after fusion coating, the aforementioned
heat treatment is conducted in a shelf dryer, jacketed tank,
jacketed mixer, jacketed vortex mixer or fluid bed. Heating
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methods are not limited. Heating temperatures vary according to
the ingredients of the matrix base material. For example, the
heat treatment may be conducted at about 40 to about 50 C for a
system containing a polyglycerol stearic acid ester and a
glycerol stearic acid ester. For a system containing a
polyglycerol behenic acid ester and a glycerol behenic acid ester,
the heat treatment may be conducted at about 40 to about 60 C,
with about 45 to about 55 C being sometimes efficient.
With respect to a pharmaceutical preparation such as
that disclosed in Japanese Patent Publication No. 2893191, i.e.,
a pharmaceutical preparation comprising core particles obtained
by spray-cooling granulation of a molten mixture of a
pharmacologically active substance and a mixture of a
polyglycerol fatty acid ester and a lipid, the release rate of
pharmacologically active substance is decreased over time once
such a pharmaceutical preparation has been stored for a certain
period of time at 40 or 50 C. This phenomenon is observable
whenever the weight ratio of polyglycerol fatty acid
ester/glycerol fatty acid ester is 50/50 to 90/10. In other words,
when a polyglycerol fatty acid ester is used in combination with
even a small amount of a glycerol fatty acid ester or other lipid,
a crystalline transition progresses during high-temperature
storage, thereby altering the rate of pharmacologically active
substance release.
In contrast, the theophylline sustained release
particles of the present invention, since the crystalline
transition of the fusion-coated particles can be enhanced and
completed by active heat treating, have a stably controlled
theophylline releasability even after long-term storage (see Test
Example 4, for example).
A-4. Dilution Process
By adding excipients and, as necessary, binders; mixing
according to known methods; and granulating and, in some cases,
compressing, the theophylline sustained release particles
obtained according to "A-3. Fusion Coating" above can be
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formulated into powders, fine powders, granules, dry syrups,
tablets and capsules.
As excipients, those that are usually used in this
technical field can be widely used in the present invention,
including mannitol, sorbitol, xylitol, erythritol, maltitol,
glucose, saccharose, lactose and like saccharides; cornstarch,
potatostarch and like starches; anhydrous calcium hydrogen
phosphate, calcium phosphate and like inorganic salts;
crystalline cellulose, sodium carboxymethyl starch; dextrin;
macrogol (e.g., polyethylene glycol 6000, polyethylene glycol
4000, etc.); etc.
As binders, those that are usually used in this
technical field can be widely used in the present invention,
including methyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, gelatin,
gum arabic, polyvinyl alcohol, pullulan, macrogol (e.g.,
polyethylene glycol 6000, polyethylene glycol 4000, etc.), a-
starch, partial a-starch, etc.
In the production of the pharmaceutical preparation
having a sustained theophylline release of the present invention
according to the method described above, disintegrators,
surfactants, lubricants, plasticizers, sweeteners, colorants and
various pharmaceutical carriers can be used in addition to the
aforementioned excipients and binders.
As disintegrators, those that are usually used in this
technical field can be widely used in the present invention,
including low-substituted hydroxypropyl cellulose, sodium
carboxymethyl starch, croscarmellose sodium, carboxymethyl
cellulose, crystalline cellulose, crospovidone, etc.
As surfactants, those that are usually used in this
technical field can be widely used in the present invention,
including sodium lauryl sulfate, polysorbate 80, sucrose fatty
acid ester, polyoxyethylene hydrogenated castor oil, etc.
As lubricants, those that are usually used in this
technical field can be widely used in the present invention,
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including magnesium stearate, calcium stearate, polyoxyl stearate,
talc, sucrose fatty acid ester, dimethyl polysiloxane, etc.
As plasticizers, those that are usually used in this
technical field can be widely used in the present invention,
including light anhydrous silicic acid and the like.
As sweeteners, those that are usually used in this
technical field can be widely used in the present invention,
including aspartame, fructose, xylitol, saccharin, sodium
saccharin, saccharose, sucrose, sorbitol, lactose, glucose,
mannitol, thaumatin, erythritol, etc.
As colorants, those that are usually used in this
technical field can be widely used in the present invention,
including coal-tar color and the like.
Flavorings such as menthol, orange flavor, etc., may be
added to the sustained-release pharmaceutical preparation of the
present invention obtained according to the method described
above.
Excipients, binders, disintegrators, lubricants,
plasticizers, sweeteners, colorants, flavorings and the like are
used in amounts suitably selected in view of the type of
medicaments used and desired resulting pharmaceutical preparation.
The theophylline sustained release particles after the
dilution process usually have an average particle diameter of 500
pm or less, preferably 410 pm or less, more preferably about 30
to about 400 pm and particularly preferably about 50 to about 400
}un .
Moreover, the theophylline sustained release particles
of the present invention have a stably controlled theophylline
releasability (dissolvability). For example, when sustained-
release particles that correspond to 100 mg theophylline are
subjected to a theophylline dissolution test according to The
Japanese Pharmacopoeia, 14th Edition, Dissolution Test (2nd Method,
Paddle Method) at a stirring speed of 75 rpm using water or 0.5%
aqueous polysorbate 80 solution as the test solution, the 2-hour
theophylline dissolution rate is about 15 to about 55%, the 4-
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hour dissolution rate is about 25 to about 70% and 6-hour
dissolution rate is about 50 to about 95%. Preferably, the 2-hour
dissolution rate is about 20 to about 50%, the 4-hour dissolution
rate is about 30 to about 65% and the 6-hour dissolution rate is
about 55 to about 90%.
The theophylline sustained release particles of the
present invention can be used as a pharmaceutical preparation in
the form of, for example, powders, fine powders, granules, dry
syrups, tablets, capsules, etc.
B. Medicament sustained release particles and Methods for
Preparing Them (second embodiment)
The medicament sustained release particles of the
present invention are in the form of a matrix formulation
containing a pharmacologically active substance, and the matrix
base material thereof has a hydroxyl value of 60 or greater. The
use of such a matrix base material allows efficient fusion
coating and the production of particulate sustained-release
matrix formulation having a stably controlled medicament
releasability. The medicament sustained release particles of the
present invention encompass core particles containing a
pharmacologically active substance in a matrix; fusion-coated
particles prepared by fusion coating such core particles with a
fine powder such as talc, a pharmacologically active substance
and the like; and similar particles that subjected to any
necessary dilution process.
B-l. Core particles
Matrix
The matrix of the core particles of the present
invention contains a matrix base material having a hydroxyl value
of 60 or greater and containing a polyglycerol fatty acid ester
as a main ingredient and, if desired, further contains ethyl
cellulose, other additives, etc. The matrix base material may
contain a glycerol fatty acid ester and the like in addition to a
polyglycerol fatty acid ester. In this case, the hydroxyl value
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of the matrix base material composed of the glycerol fatty acid
ester and the polyglycerol fatty acid ester should still be 60 or
greater.
When theophylline is used as a pharmacologically active
substance, it is preferable that the core particles contain ethyl
cellulose since the use of ethyl cellulose significantly enhances
the mixing efficiency for a molten mixture of the matrix base
material and theophylline in the preparation of core particles.
Polyglycerol Fatty Acid Esters
The polyglycerol fatty acid ester used as the matrix
base material is a fatty acid ester of a polyglycerol.
Polyglycerol fatty acid esters having a hydroxyl value of about
60 or greater are preferable.
Specific examples of polyglycerols are those that have
a polymerization degree of 2-10 and preferably 3-10. Usable are,
for example, diglycerol, triglycerol, tetraglycerol,
pentaglycerol, hexaglycerol, heptaglycerol, octaglycerol,
nonaglycerol, decaglycerol, etc. Particularly usable are
triglycerol, tetraglycerol, pentaglycerol, hexaglycerol,
heptaglycerol, octaglycerol, nonaglycerol, decaglycerol, etc.
Usable fatty acids are, for example, saturated or
unsaturated higher fatty acids having 12-22 carbon atoms and
preferably 18-22 carbon atoms. Palmitic acid, stearic acid, oleic
acid, linoleic acid, linolenic acid, myristic acid, lauric acid,
ricinoleic acid, behenic acid and the like are usable as such
fatty acids. In particular, stearic acid, oleic acid, behenic
acid, ricinoleic acid and like saturated and unsaturated higher
fatty acids having 18-22 carbon atoms are generally used.
A usable polyglycerol fatty acid ester is that in which
C12-22 fatty acid(s) are linked to the aforementioned polyglycerol
with at least 1 hydroxyl group remaining therein. Specific
examples of polyglycerol fatty acid esters are triglycerol
behenic acid esters, triglycerol stearic acid esters,
tetraglycerol behenic acid esters, tetraglycerol stearic acid
esters, pentaglycerol behenic acid esters, pentaglycerol stearic
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acid esters, hexaglycerol behenic acid esters, hexaglycerol
stearic acid esters, heptaglycerol behenic acid esters,
heptaglycerol stearic acid esters, octaglycerol behenic acid
esters, octaglycerol stearic acid esters, nonaglycerol behenic
acid esters, nonaglycerol stearic acid esters, decaglycerol
behenic acid esters, decaglycerol stearic acid esters and the
like. Such esters can be used singly or as a mixture of 2 or more
species. According to the number of hydroxyl groups in the
polyglycerol, the polyglycerol fatty acid esters are categorized
as fatty acid monoesters, diesters, triesters, tetraesters,
pentaesters, hexaesters, half esters, etc.
Among these polyglycerol fatty acid esters,
polyglycerol fatty acid half esters are preferable. In particular,
triglycerol behenic acid half esters, tetraglycerol behenic acid
half esters, pentaglycerol behenic acid half esters, hexaglycerol
behenic acid half esters, heptaglycerol behenic acid half esters,
octaglycerol behenic acid half esters, nonaglycerol behenic acid
half esters, decaglycerol behenic acid half esters and like
polyglycerol behenic acid half esters; and triglycerol stearic
acid half esters, tetraglycerol stearic acid half esters,
pentaglycerol stearic acid half esters, hexaglycerol stearic acid
half esters, heptaglycerol stearic acid half esters, octaglycerol
stearic acid half esters, nonaglycerol stearic acid half esters,
decaglycerol stearic acid half esters and like polyglycerol
stearic acid half esters are more preferably used. Triglycerol
behenic acid half esters are most preferably used.
Herein, polyglycerol fatty acid esters in which all the
hydroxyl groups in a polyglycerol are esterified with fatty acids
are referred to as polyglycerol fatty acid "full" esters, and
polyglycerol fatty acid esters in which about half of the
hydroxyl groups in the polyglycerol are esterified with fatty
acids are referred to as polyglycerol fatty acid "half" esters.
With respect to polyglycerol fatty acid esters other than the
"polyglycerol fatty acid full esters", which hydroxyl groups in
the polyglycerol are esterified are not limited; any given
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hydroxyl group may be esterified.
Specifically, a "polyglycerol fatty acid half ester"
refers to a polyglycerol fatty acid ester or a mixture thereof in
which the average number (NE) of esterified hydroxyl groups in the
polyglycerol is about the half of the number (N) of hydroxyl
groups present in the non-esterified polyglycerol. Such
polyglycerol fatty acid half esters have 0.3<NE/N-0.7, and
preferably 0.35<NE/N-<0.65.
For example, a triglycerol behenic acid half ester
means an ester in which 2 or 3 behenic acids are ester-linked to
a triglycerol having 5 hydroxyl groups, the triglycerol being 3
glycerol molecules dehydratively condensed, or a mixture thereof,
i.e., triglycerol behenic acid (di or tri) ester.
The molecular weight of the polyglycerol fatty acid
esters is usually 200-5000, preferably 300-2000 and more
preferably 500-2000. Preferable are polyglycerol fatty acid
esters that are solid at ordinary temperature (about 15 C) and
have a melting point of 15-90 C, and more preferably 45-80 C.
Such polyglycerol fatty acid esters usable herein can be a
mixture of 2 or more compounds. In such a case, even when a
liquid polyglycerol fatty acid ester is partially contained, such
a mixture is usable if it as a whole is solid at ordinary
temperatures. The core particles has a polyglycerol fatty acid
ester content of about 20 to about 99.999 wt.%, preferably about
25 to about 95 wt.% and more preferably about 30 to about 90 wt.%.
Glycerol Fatty Acid Esters
The glycerol fatty acid ester optionally used as a
secondary ingredient of the matrix base material is a C12_22 fatty
acid ester of a glycerol. Preferable glycerol fatty acid esters
include glycerol behenic acid esters, glycerol stearic acid
esters, glycerol lauric acid esters, glycerol palmitic acid
esters, etc. If necessary, 2 or more glycerol fatty acid esters
may be used in the matrix base material. Among such esters,
glycerol behenic acid esters and/or glycerol stearic acid esters
are preferable. Specific examples are glycerol stearic acid
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monoester, glycerol stearic acid diester, glycerol stearic acid
triester, glycerol behenic acid monoester, glycerol behenic acid
diester, glycerol behenic acid triester, etc. Among these,
glycerol behenic acid esters are preferable, with glycerol
behenic acid monoester, glycerol behenic acid diester and their
mixtures being especially preferable.
The core particles have a glycerol fatty acid ester
content of 0 to about 60 wt.%, preferably about 1 to about 50
wt.% and more preferably 2 to about 40 wt.%. The matrix base
material preferable in the present invention contains both a
glycerol fatty acid ester and a polyglycerol fatty acid ester.
Hydroxyl Value of Matrix base material
The matrix base material usable in the present
invention has a hydroxyl value of about 60 or greater, preferably
about 80 to about 350 and more preferably about 100 to about 300.
Due to such a hydroxyl value, the core particles can be inhibited
from electrostatically adhering to the inner walls of a
granulator in the fusion coating process described hereinbelow,
thereby allowing efficient fusion coating and the production of
particles of a matrix formulation having a stably controlled
medicament releasability. The term "hydroxyl value" as used
herein is defined in Syokuhin Tenkabutsu Kouteisho "Yushirui
Shiken Hou" (The Japanese Standards for Food Additives "Testing
Methods for Fats and Oils"), Hirokawa Shoten, 1999, B-195. In
particular, the term "hydroxyl value" refers to, when the
hydroxyl groups of a 1 g sample are acetylated, the amount (mg)
of potassium hydroxide (KOH) necessary to neutralize acetic acid
equivalent to acetyl group(s).
With respect to pharmaceutical preparations that
sustainedly release pharmacologically active substances, it is
generally considered preferable, to use polyglycerol fatty acid
esters having a low hydrophilic-lipophilic balance (HLB) for the
matrix to suppress the dissolution from the core particles.
However, when the HLB of the matrix is low, the hydroxyl value is
accordingly low, which results in a more pronounced tendency to
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electrostatically adhere to the inner walls of a granulator when
fusion coating. To prevent this electrostatic adhesion, it is
necessary to use core particles that barely accumulate an
electrostatic charge. As a solution to this problem, a matrix
base material having a hydroxyl value of preferably 60 or greater
is used.
Glycerol fatty acid esters by themselves, especially
monoglycerides (monoesters), barely adhere electrostatically to a
granulator due to their high hydroxyl values. However, glycerol
fatty acid esters and like lipids undergo crystalline transitions,
thereby making it difficult to prepare stable pharmaceutical
preparations. To inhibit crystalline transitions, it is
preferable to have in the matrix base material 50 wt.% or more
polyglycerol fatty acid ester. Therefore, the hydroxyl value of
the polyglycerol fatty acid ester in the matrix base material is
especially important. Hence, the hydroxyl value of the
polyglycerol fatty acid ester should be controlled to be
preferably about 60 or greater, more preferably about 80 to about
350 and particularly preferably about 100 to about 300.
Pharmacologically Active Substances
The pharmacologically active substances that can be
used in the medicament sustained release particles of the present
invention are not limited, and known substances can be widely
used. Examples of such pharmacologically active substances
include those typically used in a variety of pharmaceutical
preparations such as antibiotics, antifungal agents, antilipemics,
circulatory drugs, antiplatelets (platelet aggregation
inhibitors), antitumor agents, antipyretics, analgesics,
antiphlogistics, antitussive/expectorating agents, tranquillizers,
muscle relaxants, antiepileptic agents, antiulcer agents,
antidepressants, antiallergy agents, cardiac stimulants,
antiarrhythmics, vasodilators, hypotensive diuretics, diabetic
medicines, anticoagulants, hemostatic agents, antituberculosis
drugs, hormone drugs, narcotic antagonists, bone-resorption
inhibitors, vascularization inhibitors, antipodagrics, etc.
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Specific examples include theophylline, cilostazol,
grepafloxacin, carteolol, procaterol, rebamipide, aripiprazole,
etc. The group of pharmacologically active substances described
above can be used singly or in combination.
The core particles have a pharmacologically active
substance content of about 0.001 to about 60 wt.%, preferably
about 0.01 to about 55 wt.% and more preferably about 0.1 to
about 50 wt.%.
Ethyl Cellulose
Ethyl cellulose may be contained in the matrix of the
core particles of the present invention. In particular, when
theophylline is used as a pharmacologically active substance,
ethyl cellulose should be used. As described in the Disclosure of
the Invention (a), when theophylline is added to a molten mixture
prepared by heating a matrix base material containing a
polyglycerol fatty acid ester, the viscosity of the molten
mixture is excessively increased, making uniform blending
difficult. This phenomenon is peculiar to theophylline when it is
used as a medicament. However, if a small amount of ethyl
cellulose is added to the theophylline-containing molten mixture,
the viscosity of the mixture is promptly decreased, thereby
drastically improving the workability with respect to stirring,
mixing, pumping, etc., and allowing the production of a uniformly
blended molten mixture. By spray-cooling this molten mixture,
homogenous particles of a matrix formulation having a stably
controlled medicament releasability (dissolvability) can be
obtained.
The viscosity of the ethyl cellulose, determined as a
5% ethyl cellulose solution in 80% toluene and 20% ethanol (at
25 C), is usually preferably about 1 to about 100 cps, and
particularly preferably about 2 to about 50 cps.
When theophylline is used as a pharmacologically active
substance, the core particles are prepared to have an ethyl
cellulose content of about 0.01 to about 5 wt.%, preferably about
0.1 to about 3 wt.%. When the ethyl cellulose content is within
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this range, a preferable decrease in the viscosity of the molten
mixture can be observed.
Additives
Insofar as the action and effects of the present
invention are not adversely affected, additives that are
typically used in the field of sustained-release pharmaceutical
preparations can be used in the matrix of the core particles of
the present invention in addition to the compounds described
above. Examples include propylene glycol fatty acid esters,
sorbitan fatty acid esters, paraffin, microcrystalline wax,
ceresin, hydrogenated oil, Japan wax, cacao butter, carnauba wax,
beeswax, lecithin, cetanol, stearyl alcohol, myristic acid,
palmitic acid, stearic acid, titanium stearate, calcium oleate,
etc. These additives are contained in the core particles usually
in an amount of 50 wt.% or less, and preferably 40 wt.% or less.
Preferable Form of Core particles
Examples of preferable forms of the core particles of
the sustained theophylline release pharmaceutical preparation of
the present invention are given below.
Examples of pharmacologically active substances are
theophylline, cilostazol, grepafloxacin, carteolol, procaterol,
rebamipide, aripiprazole, etc., with theophylline being
particularly preferable. Although the matrix base material may be
composed of just a polyglycerol fatty acid ester, it is
preferable to also have a glycerol fatty acid ester. A
polyglycerol behenic acid half ester is preferable as the
polyglycerol fatty acid ester, and a triglycerol behenic acid
half ester is particularly preferable. A glycerol behenic acid
ester or glycerol stearic acid ester is preferable as the
glycerol fatty acid ester, and a glycerol behenic acid monoester,
a glycerol behenic acid diester and a mixture thereof are
especially preferable.
Even when such a matrix base material is used, it is
preferable to ensure 50 wt.% or greater of the entire weight of
the matrix base material in the core particles is the
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polyglycerol fatty acid ester. It is sufficient that the weight
ratio of polyglycerol fatty acid ester/glycerol fatty acid ester
in the matrix base material is about 50/50 to about 99/1, and
preferably about 50/50 to about 90/10.
The core particles have a pharmacologically active
substance content (preferably a theophylline content) of about 15
to about 50 wt.%, preferably about 20 to about 50 wt.% and more
preferably about 25 to about 45 wt.%. The core particles have a
polyglycerol fatty acid ester content of about 25 to about 80
wt.% and preferably about 30 to about 70 wt.%. The core particles
have a glycerol fatty acid ester content of about 1 to about 50
wt.%, preferably about 2 to about 40 wt.% and more preferably
about 5 to about 35 wt.%. In particularly, when theophylline is
used, the core particles should have an ethyl cellulose content
of about 0.01 to about 5 wt.% and preferably about 0.1 to about 3
wt.%.
When the core particles contain relatively low
proportions of active ingredients, the content of each ingredient
can be arranged to be in the following ranges. For example, when
the core particles contain active ingredients in about 0.001 to
about 10 wt.%, the core particles may contain the matrix base
material in about 90 to about 99.999 wt.%. When the core
particles contain active ingredients in about 0.01 to about 10
wt.%, the core particles may contain the matrix base material in
about 90 to about 99.99 wt.%. The weight ratio of polyglycerol
fatty acid ester/glycerol fatty acid ester in the matrix base
material may be 50/50 to 95/1, preferably 50/50 to 90/10.
B-2. Method for Preparing Core particles
The aforementioned core particles may be prepared as
follows:
The matrix base material containing the polyglycerol
fatty acid ester and pharmacologically active substance are
heated to a liquefied mixture (or a molten mixture) . This
liquefied mixture is spray-cooled for granulation to give
spherical core particles. The liquefied mixture includes a
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suspension mixture.
The temperature for fusing the matrix base material
containing the polyglycerol fatty acid ester is high, ranging
from the melting point (hereinafter sometimes referred to as "Tm")
of the matrix base material upwards, and preferably from (Tm
+10) C upwards, as long as such temperatures do not impair the
stability of pharmacologically active substance. When the matrix
base material is a mixture, it may not exhibit a definite melting
point. Therefore, the softening temperature (softening point,
hereinafter sometimes referred to as "T3") of the mixture can be
substituted for the aforementioned Tm.
Hereinafter, the melting point (Tm) or softening point
(Ts) of the matrix base material may sometimes be referred to as
"T", i.e., T = Tm or Ts.
To be able to uniformly dissolve (fuse) or disperse
throughout the matrix base material, a powdery pharmacologically
active substance that has an average particle diameter of about
0.1 to about 100 pun, preferably about 0.5 to about 50 pm, is
usually used.
Average particle diameters can be measured according to
known methods such as laser light scattering and the like.
Methods for heating the matrix base material and
pharmacologically active substance to give a molten mixture are
not limited. An exemplary method employed for the preparation of
the molten mixture is heating and fusing the matrix base
material; adding a pharmacologically active substance and, as
necessary, other ingredients into the molten matrix base
material; and dissolving or dispersing therein to give a molten
mixture.
The ingredients of the core particles are contained in
the amounts as described in "B-1. Core particles" above. When
theophylline is used as a pharmacologically active substance, it
is preferable to also use ethyl cellulose. The core particles are
usually prepared to have an ethyl cellulose content of about 0.01
to about 5 wt.%, preferably about 0.1 to about 3 wt.%. By the
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addition of a small amount of ethyl cellulose, the viscosity of
the molten mixture is significantly decreased, thereby allowing
easy stirring and mixing. Thus, theophylline can be uniformly
dispersed throughout the matrix base material, enabling the
preparation of homogenous particles of a matrix formulation
having a stably controlled medicament releasability
(dissolvability).
The core particles can be prepared by spray-cooling the
above-obtained molten mixture. Spray-cooling of the molten
mixture can be performed according to conventional methods using,
for example, a spray cooler equipped with a rotary disc,
pressurized spray nozzle, two-fluid spray nozzle, etc. Cooling
may usually be performed at room temperature. Appropriate control
of the spraying conditions can give the desired diameter to the
particles.
The core particles obtained according to such spray-
cooling granulation are spherical, and their average particle
diameter is usually 250 }un or less, preferably 200 pm or less,
more preferably about 30 to about 200 pm, and particularly
preferably about 50 to about 180 pm. The average particle
diameter of the core particles can be measured according to known
methods such as sieving.
Although the core particles obtained above can be used
as they are in the fusion coating process that follows, they may
be subjected to a heat treatment prior to the fusion coating. The
heat treatment conditions are a temperature from about 40 C to
about T C at which the core particles do not fuse and adhere and
a period of 2-48 hours (in particular, about 3 to about 24 hours).
Due to this heat treatment, the crystalline transition of the
matrix base material can be enhanced and completed, thereby
enabling the release of pharmacologically active substance of the
resulting product to be stabilized and thus giving sustained-
release particles excellent storage stability.
The core particles of the present invention obtained as
described above have a makeup in which a pharmacologically active
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substance is uniformly dispersed throughout the matrix.
Specifically, it is not a layered structure in which the
pharmacologically active substance is localized at or adjacent to
the surface of the matrix base material particles; rather the
pharmacologically active substance is uniformly dispersed at the
molecular level or as fine particles throughout the entire
particles of the matrix base material, i.e., at the surface and
within the particle structure.
Herein, the phrase "uniformly dispersed at the
molecular level" means that theophylline, ethyl cellulose and the
ester matrix form a homogeneous mixture of solids (solid
disper.sion). The phrase "uniformly dispersed as fine particles"
means that theophylline and ethyl cellulose are evenly scattered
as fine particles substantially throughout the entire matrix.
As described above, the core particles of the present
invention, due to the pharmacologically active substance being
uniformly dispersed throughout the matrix, can mask its
bitterness despite having an average particle diameter of about
30 to about 200 pun (preferably about 50 to about 180 pm) and so
are very small, thereby enabling a stably controlled medicament
releasability to be retained. Furthermore, the matrix base
material is present at the surface of the core particles. This
structure is suitable for fusion coating as described hereinbelow.
B-3. Fusion Coating
Fusion Coating
Fine powder is applied by fusion coating to the above-
obtained core particles to further prepare the medicament
sustained release particles of the present invention. As such a
fine powder, (a) at least one member selected from, for example,
talc, magnesium stearate, titanium oxide, ethyl cellulose,
calcium stearate and cellulose acetate, or (b) pharmacologically
active substances can be used. Examples of (b) pharmacologically
active substances are those described in "B-l. Core particles"
above. Furthermore, if necessary, to eliminate any electrostatic
charge that may build up on the particles during fusion coating,
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light anhydrous silicic acid and the like may be added. Unlike in
spray coating, organic solvents are not used in fusion coating.
When the core particles obtained according to "B-2.
Method for preparing core particles" are heated and fused, the
molten matrix base material oozes toward the nucleus particle
surface as a molten fluid. Due to the adhesiveness of the molten
fluid in this instance, any fine power present in the vicinity of
the molten fluid adheres thereto. The fusion coating employed in
the present invention is a technique to form, by taking advantage
of the adhesiveness of the molten matrix base material, a coating
(covering) layer containing fine powder on the surface of the
core particles.
The average particle diameter of the fine powder varies
according to the particle diameter of the core particles to be
fusion-coated, but it is usually smaller than the diameter of the
core particles. It is usually selected from the range of about 20
pm or smaller, preferably about 1 to about 15 pm and more
preferably about 1 to about 10 pm.
The mixing ratio of core particles and fine powder may
be determined according to the desired rate of meidcament release,
diameter of the core particles and desired particle diameter of
the end-product pharmaceutical preparation with a sustained
medicament release. The fine powder is usually used in an amount
of about 5 to about 50 parts by weight, preferably about 10 to
about 50 parts by weight and more preferably about 10 to about 45
parts by weight, per 100 parts by weight of core particles.
Fusion coating can be performed according to known
methods. For example, the fine powder may be blended with the
above-obtained core particles and heated while agitating. The
heating temperature is about the melting point (Tm) or softening
point (TS) of the matrix base material, i.e., about T. The phrase
"about T" refers to the range of (T-15) C to T C, and preferably
(T-10) C to T C. For example, when the matrix base material is
composed of a polyglycerol fatty acid ester and a glycerol fatty
acid ester, it is in the range of about 40 to about 90 C, and
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preferably about 45 to about 80 C. The duration of fusion coating
is, depending on the production scale, usually about 5 minutes to
about 5 hours.
In the present invention, the fusion coating of the
core particles with fine powder may be performed by taking
advantage of either agitating (agitation method) or a fluid bed
(fluid-bed method). When coating is performed while agitating,
conventional mixer/granulators may be used. When coating is
performed in a fluid bed, conventional fluid-bed granulators may
be used. The fusion coating is particularly preferably
performed with agitation.
In fluid beds, to heat core particles to a temperature
near their melting point, hot air having a temperature higher
than the melting point is necessary, and because of the high
temperature of the fluid-bed apparatus (side walls, meshed
portion at the bottom, etc.) the core particles fuse, adhere to
the apparatus, and cluster, resulting in impaired yields.
Moreover, it is sometimes practically impossible to tightly and
completely affix powder to the core particles for the purpose of
sustained medicament release. In contrast, when agitation method
is employed, the container temperature (jacket temperature) of
the mixer can be desirably controlled to a temperature
substantially identical to the temperature of the core particles.
Moreover, the entire apparatus can be rapidly cooled by
introducing cold water into the jacket. Therefore, the core
particles are barely overheated, completely preventing the core
particles from aggregating due to fusion and adhesion to
sidewalls.
The core particles after fusion coating are spherical
and usually have an average particle diameter of 450 pm or less,
preferably 400 dun or less, more preferably about 30 to about 400
pm and particularly preferably about 50 to about 350 pm.
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The fusion-coated particles thus obtained are
theophylline sustained release particles that have a fine-powder-
containing coating layer around their core particles.
Thermal Aftertreatment
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Although the fusion-coated particles obtained above can
be brought as they are to the process that follows, it is
preferable to subject the fusion-coated particles to a heat
treatment beforehand. The heat treatment conditions are a
temperature from about 40 C to about the melting point (softening
point) of the matrix base material at which the fusion-coated
particles do not fuse and aggregate and a period of 2-48 hours
(preferably about 3 to about 24 hours) . Due to this heat
treatment, the crystalline transition of the matrix base material
can be enhanced and completed, thereby enabling the release the
pharmacologically active substance of the resulting product to be
stabilized, and stable and extended the pharmacologically active
substance release to be maintained even after long-term storage.
Specifically, after fusion coating, the aforementioned
heat treatment is conducted in a jacketed mixer, vortex mixer or
fluid bed. Heating methods are not limited. Heating temperatures
vary according to the ingredients of the matrix base material.
For example, the heat treatment may be conducted at about 40 to
about 50 C for a system containing a polyglycerol stearic acid
ester and a glycerol stearic acid ester. For a system containing
a polyglycerol behenic acid ester and a glycerol behenic acid
ester, the heat treatment may be conducted at about 40 to about
60 C, with about 45 to about 55 C being sometimes efficient.
With respect to a pharmaceutical preparation such as
that disclosed in Japanese Patent Publication No. 2893191, i.e.,
a pharmaceutical preparation comprising core particles obtained
by spray-cooling granulation of a molten mixture of a
pharmacologically active substance and a mixture of a
polyglycerol fatty acid ester and a lipid, the release rate of
pharmacologically active substance is decreased over time once
such a pharmaceutical preparation has been stored for a certain
period of time at 40 or 50 C. This phenomenon is observable
whenever the weight ratio of polyglycerol fatty acid
ester/glycerol fatty acid ester is 50/50 to 90/10. In other words,
when a polyglycerol fatty acid ester is used in combination with
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even a small amount of a glycerol fatty acid ester or other lipid,
a crystalline transition progresses during high-temperature
storage, thereby altering the rate of pharmacologically active
substance release.
In contrast, the theophylline sustained release
particles of the present invention, since the crystalline
transition of the fusion-coated particles can be enhanced and
completed by active heat treating, have a stably controlled
theophylline releasability even after long-term storage (see Test
Example 4, for example).
B-4. Dilution Process
The sustained medicament release pharmaceutical
preparation obtained by "B-3. Fusion Coating" above may be
subjected to a dilution process. The dilution process is as
described in "A-4. Dilution Process" above.
The medicament sustained release particles of the
present invention after a dilution process usually have an
average particle diameter of 500 pm or less, preferably 410 pm or
less, more preferably about 30 to about 350 }un and particularly
preferably about 50 to about 350 pm.
Moreover, the medicament sustained release particles of
the present invention have the property of retaining an extended
release (dissolvability) of a pharmacologically active substance.
For example, when sustained-release particles that correspond to
100 mg of pharmacologically active substance are subjected to a
pharmacologically active substance dissolution test according to
The Japanese Pharmacopoeia, 14th Edition, Dissolution Test (2nd
Method, Paddle Method) at a stirring speed of 75 rpm using water
or 0.5% aqueous polysorbate 80 solution as the test solution, the
2-hour dissolution rate is about 15-550, the 4-hour dissolution
rate is about 25-70% and 6-hour dissolution rate is about 50-95%.
Preferably, the 2-hour dissolution rate is about 20-50%, the 4-
hour dissolution rate is about 30-65% and the 6-hour dissolution
rate is about 55-90%.
The medicament sustained release particles of the
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present invention can be used as a pharmaceutical preparation in
the form of, for example, powders, fine powders, granules, dry
syrups, tablets, capsules, etc.
BEST MODE FOR CARRYING OUT THE INVENTION
Examples are given below to illustrate the present
invention in more detail, but the scope of the invention is not
limited to these examples. The symbols in the tables mean
"wt.o" unless specified otherwise.
<Ingredients used in the examples>
Theophylline
Poem B-100 : Riken Vitamin Co., Ltd., glycerol behenic acid
monoester
Poem B-200 : Riken Vitamin Co., Ltd., glycerol behenic acid ester
(including mono- and diesters)
Glycerol monostearic acid ester P-100: Riken Vitamin Co., Ltd.,
glycerol monostearic acid ester
J-46B: Riken Vitamin Co., Ltd., tetraglycerol hexabehenic acid
ester
TR-HB: Riken Vitamin Co., Ltd., triglycerol behenic acid half
ester
TR-FB: Riken Vitamin Co., Ltd., triglycerol behenic acid full
ester
TR-2B: Riken Vitamin Co., Ltd., triglycerol monobehenic acid
ester
DI-FB: Riken Vitamin Co., Ltd., diglycerol behenic acid full
ester
DDB-750: Sakamoto Yakuhin Kogyo Co., Ltd., decaglycerol
heptabehenic acid ester
HB-750: Sakamoto Yakuhin Kogyo Co., Ltd., decaglycerol
dodecabehenic acid ester
Ethyl cellulose (EC) (7 cps): Dow Chemical Company, ethyl cellulose
7 cps
Ethyl cellulose (EC) (10 cps)-FP: Dow Chemical Company, ethyl
cellulose 10 cps-FP
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Talc
Light anhydrous silicic acid
Sucrose (ground)
D-mannitol
Polysorbate 80
Sodium lauryl sulfate
Test Example 1 (Reduction in the viscosity of molten mixture by the
addition of EC)
A polyglycerol fatty acid ester and, as necessary, a
glycerol fatty acid ester were heated and fused. A medicament
(theophylline, rebamipide or cilostazol) was dispersed therein
using a homogenizer. The viscosity of the molten mixtures was
measured by a model C viscometer. Likewise, molten mixtures were
prepared in the same manner except that EC (7 cps) or cellulose
acetate was further added. The viscosity of these molten mixtures
was also measured. Tables 1-6 below show the results of Examples
1-12, Comparative Examples 1-9 and Reference Examples 1-7.
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Table 1
Ex. 2 Ex. 3 Ex. 4
Comp. Ex. 1 Ex.
Ex. Theophylline 40.0% 39.7% 40% 40% 39.2% 39.5%
EC(7cps) 0.0% 0.7% 0% 1% 2.0% 3.1%
B-100 0.0% 0.0% 30% 30% 29.4% 28.7%
TR-HB 60.0% 59.6% 30% 29% 29.4% 28.7%
Total 100.0% 100.0% 100% 100% 100.0% 100.0%
Viscosity 4000 2000 1200 320-360 400 600-M0
(mPa=s)
Table 2
Comp. Ex. Ex. 5 Comp. Ex. Ex. 6 Ex. 7 Ex. 8
Theophylline 40% 40% 40.0% 40.0% 40.0% 40.0%
EC(7cps) 0% 1% 0.0% 1.0% 3.0% 5.0%
B-100 0% 0% 18.3% 18.0% 17.4% 16.8%
HB-750 60% 59% 41.7% 41.0% 39.6% 38.2%
Total 100% 100% 100.0% 100.0% 100.0% 1002V
Viscosity 3800 1600 900 420 440 600
(mPa=s)
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Table 3
Comp.
Co. 5 Ex. 9 Ex. 10 Ex. 11 Ex. 12
Theophylline 40.0% 39.9% 39.7% 40.1% 40.0%
EC(7cps) 0.0% 0.3% 0.7% 1.3% 3.0%5
DDB-750 60.0% 59.8% 59.6% 58.6% 57.0%
Total 100.0% 100.0% 100.0% 100.0% 100.0%
Viscosity (mPa=s) 1160 480 460 540 880
Table 4
Comp. Ex. 6 Comp. Ex. 7 Comp. Ex. Comp. Ex. 9
Theophylline 40.0% 39.9% 39.7% 40.1%
Cellulose acetate 15
(10 NF) 0.0% 0.3% 0.7% 1.3%
TR-HB 60.0% 59.8% 59.6% 58.6%
Total 100.0% 100.0% 100.0% 100.0%
Viscosity (mPa=s) 1520 1560 1640 1960
*: a product in conformity with USP/NF of U.S.A.
Table 5
Ref. Ex. 1 Ref. Ex. 2 Ref. Ex. 3
Rebamipide 35.7% 35.6% 35.5%25
EC(7cps) 0.0% 0.4% 0.7%
TR-HB 64.3% 64% 63.8%
Total 100.0% 100.0% 100.0%
Viscosity 1320 1400 1520 30
(mPa=s)
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Table 6
Ref. Ex. 4 Ref. Ex. 5 Ref. Ex. 6 Ref. Ex. 7
Cilostazol 10.0% 9.9% 9.9% 9.7%
EC(7cps) 0.0% 0.7% 1.4% 2.8%
B-100 28.6% 28.4% 28.2% 27.8%5
J-46B 61.4% 61.0% 60.5% 59.7%
Total 100.0% 100.0% 100.0% 100.0%
Viscosity (mPa=s) 920 860 780 820
When the results of Comparative Example 1 and Example 1
shown in Table 1 and the results of Comparative Example 3 and
Example 5 shown in Table 2 are considered, the effect of ethyl
cellulose in decreasing viscosity is evident. In other words, when
the matrix base material is composed only of a polyglycerol fatty
acid ester (TR-HB or HB-750), the molten mixtures exhibited high
viscosity (4000 for Comparative Example 1 and 3800 for Comparative
Example 3) . Hence, it was difficult to uniformly disperse the
medicament in the respective matrices. In contrast, when a small
amount. of EC was added, the viscosity of the molten mixtures was
greatly decreased (2000 for Example 1 and 1600 for Example 5).
In view of the results of Comparative Example 2 and
Examples 2-4 shown in Table 1 and the results of Comparative
Example 4 and Examples 6-8 shown in Table 2, when the matrix base
material is composed of a polyglycerol fatty acid ester (TR-HB or
HB-750) and a glycerol behenic acid ester (B-100), the molten
mixtures exhibited high viscosity. However, when a small amount of
EC was added, the viscosity of the molten mixtures was greatly
decreased.
Considering the results shown in Tables 1-3, it is
preferable to add EC in a specific proportion relative to the
molten mixture. When the amount of EC is excessive, viscosity is
increased. In other words, when the proportion of theophylline,
polyglycerol fatty acid ester, and, as necessary, glycerol fatty
acid ester contained in the molten mixture stays constant, a
significant decrease in the viscosity of the molten mixture can be
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observed with the addition of a specific proportion of EC.
As shown in Table 4, when cellulose acetate was used in
place of EC, a decrease in the viscosity of the molten mixtures was
not observed.
As shown in Tables 5 and 6, when other pharmacologically
active substances (i.e., rebamipide and cilostazol) were used in
place of theophylline, a decrease in the viscosity of the molten
mixtures was not observed. That is, only when EC is added to
molten mixtures containing a polyglycerol fatty acid ester and
theophylline, is the viscosity of the molten mixtures decreased.
When ethyl cellulose was added to a molten mixture
containing a medicament other than theophylline, and a polymer
other than ethyl cellulose was added to a molten mixture containing
theophylline, a decrease in the viscosity was not observed.
Examples 13-18 (Preparation of core particles)
In view of the results of Test Example 1, the core
particles of Example 13 were prepared as follows: 6750 g of
triglycerol behenic acid half ester (hydroxyl value: 130, trade
name: TR-HB) and 1800 g of glycerol monobehenic acid ester
(hydroxyl value: 280, trade name: Poem B-100) were heated and fused,
and 450 g of ethyl cellulose (7 cps, manufactured by Dow Chemical
Company) and 6000 g of theophylline were mixed thereinto to give 15
kg of a molten mixture. This molten mixture was spray-cooled by a
spray cooler equipped with a rotary disc having a diameter of 2.5
m (ODT-25, manufactured by Okawara Mfg Co., Ltd.) at an atomizer
speed of 15000 rpm, and the particles thus obtained were screened
with a 355 pm sieve, thereby giving theophylline-containing core
particles with an average particle diameter of 130 pm.
Examples 14-18, the results of which are shown in Table
7, were conducted in the same manner as Example 13 to prepare
similar core particles.
In all cases, the molten mixtures could be mixed
efficiently, and theophylline-containing core particles in which
ingredients were uniformly dispersed were obtained.
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Table 7
Ex. 13 Ex. 14 Ex. 15 Ex. 16 Ex. 17 Ex. 18
Theophylline (o) 40 40 40 40 40 40
TR-HB(%) 45 51 30 41 41 41
B-100(%) 12 6 27 18 145
P-100 (o) 18 4
EC(o) 3 3 3 1 1 1
Total(o) 100 100 100 100 100 100
Test Example 2 (Relationship between hydroxyl value and
electrostatic adhesion)
Using particles of low-melting-point substances
containing no pharmacologically active substances as core particles,
the relationship between hydroxyl value and electrostatic adhesion
of the core particles in fusion coating was investigated.
Particles of a low-melting-point substance (750 g) and
talc (105 g) were charged into a jacketed high-shear
mixer/granulator (vertical granulator, FM-VG-05, manufactured by
Powrex Corporation) and agitated while heating at a jacket
temperature of about 70 C to carry out fusion coating. Once the
fine powder of talc had disappeared, water was introduced into the
jacket for cooling, thereby giving the fusion-coated particles of
Reference Example 8.
For Reference Examples 9-11 and Comparative Reference
Examples 1 and 2, fusion coating was conducted in the same manner
as above. The extent of electrostatic adhesion of the core
particles to the inner walls of the granulator is shown in Table 8.
Table 8 shows that in the fusion coating of Comparative
Reference Examples 1 and 2 wherein the hydroxyl value of the
particles is low, the electrostatic adhesion of the core particles
to the inner walls of the granulator was extremely severe,
resulting in a poor product yield, i.e., not giving the desired
particles satisfactorily.
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Table 8
Ref. Ex. Ref. Ex. RCom . Comp. Ref. Ref. Ex. Ref. Ex.
8 9 I Ex. Ex. 2 10 11
Core
particles TR-2B TB-82 J-46B DI-FB Poem TR-HB
Hydroxyl 190 70 15 18 190 132
value
Terminal
temperature 68 68 67 68 65 68
of heating
( C)
Extent of minimal little severe severe minimal minimal
adhesion ( ) (+) (+++) (+++) ( ) ( )
Examples 19-21 (Fusion coating: talc plus EC)
In view of the results of Test Example 2, 750 g of the
core particles obtained in Example 17, 18 g of ethyl cellulose (10
cps-FP, manufactured by Dow Chemical Company) and 162 g of talc
were charged into a jacketed high-shear mixer/granulator (vertical
granulator, FM-VG-05, manufactured by Powrex Corporation) and
agitated while heating at a jacket temperature of about 70 C to
carry out fusion coating. Once the talc and EC had adhered to the
core particles, the particles were cooled by reducing the jacket
temperature, thereby giving fusion-coated particles. After adding
and mixing light anhydrous silicic acid, the particles thus
obtained were screened with a 355 pm sieve, thereby giving the
sustained-release particles of Example 19.
For Examples 20 and 21, fusion coating was conducted in
the same manner as above.
In the fusion coating of Examples 19-21, electrostatic
adhesion of the core particles to the inner walls of the
granulator did not occur at all, giving a product yield of about
990.
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Table 9
Example Ex. 19 Ex. 20 Ex. 21
Core particles prepared
Ex. 17 Ex. 17 Ex. 17
in
Weight of core particles 750 750 750
(g)
EC (10 cps-FP) (g) 18 36 0
Talc (g) 162 144 180
Light anhydrous 1.5 1.5 1.5
silicic acid (g)
Total (g) 931.5 931.5 931.5
Examples 22-32 (Fusion coating: talc)
Using the formulations shown in Tables 10 and 11, core
particles (750 g) and talc were charged into a jacketed high-shear
mixer/granulator (vertical granulator, FM-VG-05, manufactured by
Powrex Corporation) and agitated while heating at a jacket
temperature of about 70 C to carry out fusion coating. Once the
talc had adhered to the core particles, the particles were cooled
by reducing the jacket temperature, thereby giving fusion-coated
particles. After adding and mixing light anhydrous silicic acid,
the particles thus obtained were screened with a 355 pm sieve,
thereby giving sustained-release particles.
In the fusion coating of Examples 22-32, electrostatic
adhesion of the core particles to the inner walls of the
granulator did not occur at all, giving a product yield of about
99%.
In Tables 10 and 11, "talc (%)" refers to the weight %
of talc coating relative to the weight of core particles.
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Table 10
Example Ex. 22 Ex. 23 Ex. 24 Ex. 25 Ex. 26
Core particles Ex. 13 Ex. 16 Ex. 16 Ex. 16 Ex. 16
prepared in
Weight of core 750 750 750 750 750
particles (g) 5
Talc (g) 210 240 120 300 112.5
Light anhydrous
1.5 1.5 1.5 1.5 1.5
silicic acid (g)
Total weight (g) 961.5 991.5 871.5 1051.5 864
Talc (%) 28% 32% 16% 40% 15%
Table 11
Example Ex. 27 Ex. 28 Ex. 29 Ex. 30 Ex. 31 Ex. 32
Core particles Ex. 14 Ex. 16 Ex. 14 Ex. 15 Ex. 16 Ex. 16
prepared in
Weight of core 750 750 750 750 750 750
particles (g)
Talc (g) 120 150 150 270 112.5 187.5
Light anhydrous
1.5 1.5 1.5 1.5 1.5 1.5
silicic acid (g)
Total weight (g) 871.5 901.5 901.5 1021.5 864 939
Talc (%) 16% 20% 20% 36% 15% 25%
Examples 33-36 (Fusion coating: talc)
15 Using the formulations shown in Table 12, core
particles (750 g) and talc were charged into a jacketed high-shear
mixer/granulator (vertical granulator, FM-VG-05, manufactured by
Powrex Corporation) and agitated while heating at a jacket
temperature of about 70 C to carry out fusion coating. Once the
20 talc had adhered to the core particles, the particles were cooled
by reducing the jacket temperature, thereby giving fusion-coated
particles. After adding and mixing light anhydrous silicic acid,
the particles thus obtained were screened with a 355 pun sieve,
thereby giving sustained-release particles.
25 In the fusion coating of Examples 33-36, electrostatic
adhesion of the core particles to the inner walls of the
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granulator did not occur at all, giving a product yield of about
990.
In Table 12, "talc (%)" refers to the weight % of talc
coating relative to the weight of core particles.
Table 12
Ex. 33 Ex. 34 Ex. 35 Ex. 36
Core particles prepared Ex. 17 Ex. 17 Ex. 17 Ex. 18
in
Weight of core 750 750 750 750
particles (g) 10
Talc (g) 150 112.5 225 187.5
Light anhydrous
1.5 1.5 1.5 1.5
silicic acid (g)
Talc (%) 20% 15% 30% 25%
Comparative Example 17 (Matrix base material having a low
hydroxyl value)
Triglycerol behenic acid full ester TR-FB (8400 g,
hydroxyl value: 15) was heated and fused, mixed with 1200 g of EC
and 6400 g of theophylline, and granulated by spray cooling,
thereby giving core particles having an average particles diameter
of 130 pm. These core particles (700 g) and talc (350 g) were
mixed and charged into a jacketed high-shear mixer/granulator
(vertical granulator, FM-VG-05, manufactured by Powrex Corporation)
and agitated while heating at a jacket temperature of about 70 C to
carry out fusion coating.
During heating, talc, before thoroughly adhering to the
core particles, was electrostatically adhered to the inner walls
of the granulator. When heating and agitating were continued, the
core particles were melted and adhered onto the inner walls,
resulting in particles with incomplete fusion coating.
Test Example 3
A dissolution test was carried out using the fusion-
coated particles obtained in Comparative Example 17.
This dissolution test was carried out according to The
Japanese Pharmacopoeia, 14th Edition, Dissolution Test (2nd Method,
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Paddle Method). Test conditions included paddle stirring speed:
75 rpm, test solution: 900 ml 0.5% aqueous polysorbate 80
solution, and sample theophylline: a particulate pharmaceutical
preparation corresponding to 100 mg theophylline. Figure 1 shows
the results.
As is clear from Figure 1, the fusion-coated particles
of Comparative Example 17 do not exhibit a controlled (sustained)
theophylline release.
Test Example 4 (Heat treatment)
The fusion-coated particles obtained in Example 28 were
subjected to a heat treatment at 50 C for 12 hours, and then
cooled to room temperature. These particles were filled into
glass bottles and stored at 50 C for 2 months. The results of
dissolution tests conducted for the particles immediately after
heat treatment (before storage), after 1-month storage and after
2-month storage show that the release rates for the particles
before storage (after heat treatment) and after storage were not
significantly different (see Figure 2).
The aforementioned dissolution tests were conducted
according to The Japanese Pharmacopoeia, 14th Edition, Dissolution
Test (2nd Method, Paddle Method) under the same conditions as in
Test Example 3.
In contrast, the fusion-coated particles obtained in
Example 25 without heat treatment were filled into glass bottles
and stored at 40 or 50 C. The results of dissolution tests
conducted as above for the particles after fusion coating (before
storage), after 2-week storage and after 1-month storage
demonstrate, as shown in Figure 3, that the post-storage
particles exhibit a decrease in dissolution rate compared with
such particles before storage. This is presumably because the
matrix base material of the fusion-coated particles undergoes
crystalline transition during the storage.
Furthermore, the fusion-coated particles obtained in
Example 28 without heat treatment were filled into glass bottles
and stored at 40 or 50 C. The results of dissolution tests
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conducted as above for the particles after fusion coating (before
storage), after 2-week storage and after 2-month storage
demonstrate, as shown in Figure 4, that the post-storage
particles exhibited a decrease in dissolution rate compared with
the particles before storage. This is presumably because the
matrix base material of the fusion-coated particles undergoes
crystalline transition during the storage.
Test Example 5 (Fusion coating by agitation method and fluid-bed
method)
The core particles obtained in Example 16 (800 g) and
talc (160 g) were charged into a fluid-bed granulator (MP-01,
manufactured by Powrex Corporation) to conduct fusion coating.
Air was supplied at 75-90 C to heat and fluidize. After the
product was heated to 67 C, the air supply heater was turned off
to gradually cool, thereby giving fusion-coated particles. When
these particles were taken out, adhesion of fused matter to the
meshed portion at the lower part of the container was observed,
and there were many coarse particles. The recovered particles
were screened with a 355 pm sieve and mixed with 1.5 g light
anhydrous silicic acid to give the fluid-bed-fusion-coated
particles of the present invention.
The particles of Example 28 fusion-coated by agitation
method and the aforementioned particles fusion-coated by fluid-
bed method were subjected to dissolution tests. Dissolution tests
were conducted according to The Japanese Pharmacopoeia, 14th
Edition, Dissolution Test (2"d Method, Paddle Method) under the
same conditions in Test Example 3. Figure 5 shows the results.
As shown in Figure 5, the particles of Example 28
fusion-coated by agitation method, compared with the particles
fusion-coated by fluid-bed method, exhibited a significantly-
enhanced sustained theophylline release.
Example 37 (Dilution process)
The fusion-coated particles obtained in Example 27
(290.5 g), sucrose (100.5 g) and D-mannitol (70 g) were charged
into a fluid-bed granulator (MP-01, manufactured by Powrex
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Corporation) for fluid-bed granulation using an aqueous sucrose
solution as a binder solution. The particles thus obtained were
dried, screened with a 850 pim sieve and mixed with 0.5 g light
anhydrous silicic acid, thereby giving theophylline sustained
release particles of the present invention.
Example 38 (Dilution process)
The fusion-coated particles obtained in Example 32 (313
g), sucrose (90 g) and D-mannitol (55 g) were charged into a
fluid-bed granulator (MP-01, manufactured by Powrex Corporation)
for fluid-bed granulation using an aqueous solution of 80 g
sucrose and 2 g polysorbate 80 as a binder solution. The
particles thus obtained were dried, screened with a 850 pm sieve
and mixed with 0.5 g light anhydrous silicic acid, thereby giving
theophylline sustained release particles of the present invention.
Example 39 (Dilution process)
The fusion-coated particles obtained in Example 28
(300.5 g), sucrose (95 g) and D-mannitol (63.5 g) were charged
into a fluid-bed granulator (MP-01, manufactured by Powrex
Corporation) for fluid-bed granulation using an aqueous solution
of 120 g sucrose and 1.5 g polysorbate 80 as a binder solution.
The particles thus obtained were dried, screened with a 850 pm
sieve and mixed with 0.5 g light anhydrous silicic acid, thereby
giving theophylline sustained release particles of the present
invention.
Example 40 (Dilution process)
The fusion-coated particles obtained in Example 29
(300.5 g), sucrose (105 g) and D-mannitol (73.5 g) were charged
into a fluid-bed granulator (MP-01, manufactured by Powrex
Corporation) for fluid-bed granulation using an aqueous solution
of 40 g sucrose and 1 g polysorbate 80 as a binder solution. The
particles thus obtained were dried, screened with a 850 pm sieve
and mixed with 0.5 g light anhydrous silicic acid, thereby giving
theophylline sustained release particles of the present invention.
Example 41 (Dilution process)
The fusion-coated particles obtained in Example 31 (288
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g), sucrose (101.5 g) and D-mannitol (80 g) were charged into a
fluid-bed granulator (MP-01, manufactured by Powrex Corporation)
for fluid-bed granulation using an aqueous solution of 30 g
sucrose and 0.5 g sodium lauryl sulfate as a binder solution. The
particles thus obtained were dried, screened with a 850 pm sieve
and mixed with 0.5 g light anhydrous silicic acid, thereby giving
theophylline sustained release particles of the present invention.
Example 42 (Dilution process)
The fusion-coated particles obtained in Example 33 (313
g), sucrose (100 g) and D-mannitol (81.5 g) were charged into a
fluid-bed granulator (MP-01, manufactured by Powrex Corporation)
for fluid-bed granulation using 4% aqueous hydroxypropyl
cellulose solution as a binder solution. The particles thus
obtained were dried, screened with a 850 pm sieve and mixed with
0.5 g light anhydrous silicic acid, thereby giving theophylline
sustained release particles of the present invention.
EFFECTS OF THE INVENITON
According to the method for preparing the theophylline
sustained release particles of the present invention, by adding
ethyl cellulose to a molten mixture of a polyglycerol fatty acid
ester and theophylline, the viscosity of the molten mixture is
decreased, thereby enhancing mixing efficiency.
Moreover, according to the method of the invention, the
use of fusion coating performed by agitation enables the
production of the desired fusion-coated particles in a high yield
without having molten matter adhered on apparatus walls, unlike
with fluid-bed fusion coating.
Furthermore, according to the method of the invention,
fusion-coated particles may be subjected to a heat treatment to
enhance and complete crystalline transition, enabling the
production of a stable pharmaceutical preparation whose release
rate does not changed over time.
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The theophylline sustained release particles of the
present invention obtained according to the aforementioned method
are a homogenous matrix formulation in which theophylline is
uniformly dispersed that has a superior sustained medicament
releasability (dissolvability) and excellent storage stability.
Moreover, it effectively masks the unpleasant taste of the
medicament.
Furthermore, in the present invention, a matrix base
material having a specific hydroxyl value is used. Therefore,
when a fine powder is applied to core particles by fusion coating,
the core particles are effectively prevented from
electrostatically adhering to the inner walls of a
mixer/granulator which may occur due to the matrix base material,
enabling efficient production of a particulate pharmaceutical
preparation having a sustained medicament release.
